Proteases, Their Receptors and Their Role in Intestinal Epithelial Homeostasis

The maintenance of intestinal epithelial homeostasis is essential to the physiological functions of the gut, including host defence and the regulation of permeability. Loss of homeostasis, often resulting in epithelial barrier dysfunction, is a key factor in many inflammation-associated diseases of the gastrointestinal tract, including inflammatory bowel disease, enteric infections, radiation enteritis, among others. The intestinal epithelium is exposed to a wide variety of proteases, many of which can induce specific signaling responses through mechanisms that are either receptor-independent or dependent upon activation of protease-activated receptors (PARs). We have been investigating how proteases and their receptors regulate epithelial homeostasis by (1) enhancing barrier function, (2) regulating epithelial cell migration, and (3) inhibiting epithelial cell apoptosis. Enhancing Barrier Function. Apical exposure to serine proteases enhances the barrier function of epithelia, rendering them less permeable to bacteria, bacterial products and antigens. We have shown that the enhanced barrier function is due to rapid occludin-dependent remodeling of the tight junction, an effect that is independent of the activation of PARs. Our studies have uncovered the signaling pathways that mediate this effect, and we are determining the role that serine proteases may play in preventing the barrier dysfunction caused by inflammatory cytokines. Regulating epithelial migration. We have shown that PAR2 (activated by trypsin and other serine proteases) can modulate epithelial migration in wound healing assays in epithelial cell culture systems. We will show the data that defines the pathways that mediate this effect and discuss the implications for PAR agonists as mediators of wound healing as a facet of maintaining epithelial homeostasis. Inhibition of apoptosis. Death by apoptosis is the normal fate of intestinal epithelial cells, but is up-regulated in inflammation. Preventing excessive apoptotic death is a key element of epithelial homeostasis. We have shown that PAR2 activation modulates cell survival pathways to limit apoptosis caused by IFN[gamma] and TNF[gamma]. Understanding proteases and the pathways by which they contribute to epithelial homeostasis may reveal new therapeutic targets to help patients with diseases characterized by intestinal inflammation or injury.